Abstract
Background/Aims
Biochemical parameters and acute-phase proteins (APPs) may provide complementary data in patients with chronic hepatitis C (CHC). We aimed to evaluate the predictive role of APPs in the response to antiviral therapy.
Methods
Forty-five patients underwent antiviral therapy. Serum ferritin, C-reactive protein (CRP), transferrin, albumin, alpha-1 acid glycoprotein (A1AG), and alpha-2 macroglobulin (A2MG) levels were examined at the initial evaluation and at the 4th, 12th, and 48th weeks. HCV RNA levels were examined at the initial evaluation and at the 12th and 48th weeks.
Results
Ferritin, transferrin, A1AG, and A2MG levels were significantly higher in the patient group (p<0.05). CRP, ferritin, A1AG, and A2MG levels were significantly increased from baseline to the 4th week (p<0.05). The responders and nonresponders to antiviral therapy had insignificantly but remarkably different levels of CRP, ferritin, transferrin, A1AG, A2MG, and alanine aminotransferase (ALT) both at the initial evaluation and at the 12th week.
Conclusions
Variations in ferritin, A1AG, A2MG, albumin, CRP, and transferrin levels are not alternatives to virological and biochemical parameters for predicting an early response to therapy in patients with CHC. However, the investigation of ALT levels and hepatitis C virus RNA in combination with acute-phase reactants may provide supplementary data for evaluating responses to antiviral therapy.
Keywords: Hepatitis C, Acute-phase proteins, Hepatitis C virus RNA
INTRODUCTION
Chronic hepatitis C (CHC) virus infection; one of the most frequent cause of cirrhosis and hepatocellular carcinoma (HCC), is a public health problem for all races and has become the most common cause of death associated with liver disesase.1 It is suggested that 300 million people is infected by hepatitis C virus (HCV) worldwide and the prevalence of anti-HCV positivity in Turkish population is 1.8%.2 A majority of patients infected with HCV do not spontaneously clear the virus and become chronically infected. More than 80% of all HCV infected patients will develop chronic hepatitis, and in 20% of this patients will lead to liver cirrhosis.3
CHC, associated with liver cell necrosis, inflammation, regeneration, fibrosis, and cirrhosis has been recognized as an important risk factor for the development of HCC.4 Accumulation of iron and serum iron levels are strongly correlated with hepatic fibrosis and inflammatory activity. The presence of increased hepatic iron, which is present in 30% to 40% of patients with CHC, has been linked to more severe liver disease and poorer response to interferon (IFN) monotherapy.5 The clinical course of HCV infection is influenced with iron storage which leads to hepatic dysfunction and macrophage activation.6 Serum ferritin levels represents the severity of hepatic fibrosis independent from the liver iron accumulation.7 Alpha-2 macroglobulin (A2MG), an acute-phase proteins (APP), is synthesized in hepatocytes and stellate cells.8 A2MG inhibits the catabolism of matrix proteins and fibrotic process and both hepatic and serum levels of alpha-1 acid glycoprotein (A1AG) increases in fibrogenetic environment.9
The aim of this study was to evaluate the predictive role of APPs in response to antiviral therapy.
MATERIALS AND METHODS
This study was conducted between May 2004 and May 2005 in Department of Gastroenterology, Gaziantep University Faculty of Medicine. Forty-five patients with CHC virus infection and 30 healthy individuals were enrolled. Inclusion criteria for patients group were; elevated alanine aminotransferase (ALT) levels for more than 6 months, anti-HCV positivity and HCV RNA level exceeding 200 IU/mL and moderate to severe necroinflammatory activity and fibrosis stage of 2 to 6/6. Entire patients were in genotype 1b and none of participants had a history of antiviral therapy. Control group consisted of healthy subjects with negative anti HCV. Patients and controls with concomittant disorders like congestive heart failure, chronic renal failure, psychosis, pregnancy, hematological disorders, decompansated liver cirrhosis, and combined hepatitis C+B or C+B+D virus infection were excluded.
Diagnosis of CHC is confirmed by biochemical, serological, and histopathological examination. Modified Knodell scoring system was used for histopathological assessment. Patients with CHC received pegIFN-a-2a 180 µg/wk subcutaneously, plus oral ribavirin at a dose of 1,000 to 1,200 mg/day. HCV-RNA levels were examined at the 12th week of treatment. Treatment was continued if HCV-RNA was negative or a decrease of 2 log or more in HCV RNA level was achieved. Nonresponders were described as patients with a decrease less than 2 log in HCV RNA levels at the 12th week. Also patients with positive HCV RNA at the 24th week were accepted as nonresponders; treatment was continued up to 48th week for patients with negative HCV RNA at the 24th week.10-12
Total blood count and biochemical analysis were carried out in every outpatient clinic visit. Serum ferritin, C reactive protein (CRP), transferrin, albumin, A1AG, and A2MG levels were examined at the 4th, 12th, and 48th weeks. Serum HCV RNA levels were quantitatively analyzed at 12th, 24th, and 48th weeks.
Biochemical parameters were spectrometrically examined by Modular System Otoanalyser (Roche Diagnostic, Basel, Switzerland). Ferritin levels were assessed by Roche E-170 Modular System Electro Chemiluminecance. Serologic parameters including anti-HCV, HBsAg, anti-HBs, and autoantibodies (antinuclear antibody, smooth muscle antibodies, liver-kidney microsome type 1) were analyzed by ELISA method. PCR hybridization was used to determine HCV RNA levels. CRP, A1AG, A2MG, transferrin levels were analyzed nephelometrically by Nephelometer 100 analyser (Dade Behring, Deerfield, IL, USA).
In accordance with Declaration of Helsinki, patients were informed and informed constant was obtained.
Statistical analysis
Student's t-test was used to calculate mean values. Grouped data were evaluated for significance using chi-squared test, and Fisher's exact test. A p-value of smaller than 0.05 was considered to be statistically significant difference between the compared groups. Correlation of data was performed by Pearson's test.
RESULTS
Table 1 indicates the demographic features and biochemical parameters of patients and control group. Ferritin, transferrin, A1AG, and A2MG levels were significantly higher in patients group (p<0.05) (Table 2). Difference was nonsignificant between groups in terms of CRP and albumin levels.
Table 1.
Clinical and Demographic Features of Patients and Control Group
Data are presented as mean±SD.
ALT, alanin aminotransferase; AST, aspartat aminotransferase; GGT, gamma glutamyl transferase; ALP, alkaline phosphatase; WBC, white blood cell; HAI, histological activity index; HCV RNA, hepatitis C virus RNA.
Table 2.
Acute Phase Proteins Level of Patients and Control Group
Data are presented as mean±SD.
CRP, C-reactive protein; A1AG, alpha-1 acid glycoprotein; A2MG, alpha-2 macroglobulin.
CRP levels were significantly elevated from initial evaluation to 4th and 12th week of therapy (p<0.05). However, significant elevation did not remain stable at the 48th week. Ferritin levels were significantly decreased from 4th to 12th week and to 48th week; however, it was still significantly higher than baseline point (p<0.05). A1AG levels were significantly increased between 4th, 12th, and 48th week (p<0.05). A2MG levels were significantly decreased from baseline point to 4th and to 12th week (p<0.05); however, significant decrease did not remain stable between baseline point and 48th week. Transferrin levels were nonsignificantly decreased from baseline point to 4th week; however, there was a nonsignificant elevation of transferrin levels between baseline point and 12th week. Significant decrease in transferrin levels from baseline evaluation to 48th week was observed (p<0.05). Difference of albumin levels between baseline point and 4th, 12th, and 48th week were nonsignificant. Reduction of ALT levels between baseline point and 4th, 12th, and 48th week were significant (p<0.05). Reduction of HCV RNA levels between baseline point and 12th and 48th week were also significant (p<0.05) (Table 3).
Table 3.
Mean Variations of Acute Phase Proteins and ALT Levels at Initial Point, 4th, 12th, and 48th Week and HCV RNA Levels at Initial Point,12th and 48th Week of Patients Group
Data are presented as mean±SD.
ALT, alanine aminotransferase; HCV RNA, hepatitis C virus RNA; CRP, C-reactive protein; A1AG, alpha-1 acid glycoprotein; A2MG, alpha-2 macroglobulin.
CRP, ferritin, transferrin, A1AG, A2MG, and ALT levels of responders (n=37) and nonresponders (n=8) to treatment were nonsignificantly different (p>0.05). Albumin and HCV RNA levels were decreased remarkably but nonsignificantly (p=0.054 vs p=0.055, respectively) (Table 4).
Table 4.
Mean Acute Phase Proteins, ALT, and HCV RNA Levels of Responders and Nonresponders to Treatment at Initial Point
Data are presented as mean±SD.
ALT, alanine aminotransferase; HCV RNA, hepatitis C virus RNA; CRP, C-reactive protein; A1AG, alpha-1 acid glycoprotein; A2MG, alpha-2 macroglobulin.
There was no significant difference between CRP, ferritin, transferrin, A1AG, A2MG, albumin, and ALT levels of responders (n=37) and nonresponders (n=8) at 12th week (p>0.05). However, HCV RNA levels were significantly different (p<0.01) (Table 5).
Table 5.
Acute Phase Proteins, ALT, and HCV RNA Levels of Responders and Nonresponders to Treatment at 12th Week
Data are presented as mean±SD.
ALT, alanine aminotransferase; HCV RNA, hepatitis C virus RNA; CRP, C-reactive protein; A1AG, alpha-1 acid glycoprotein; A2MG, alpha-2 macroglobulin.
There was a positive correlation between HCV RNA and CRP, ferritin, A2MG, albumin levels at the 12th week; however, it was statistically nonsignificant (r=0.01, r=0.27, r=0.19, r=0.08, respectively; p>0.05). ALT and CRP, ferritin, transferrin, A2MG levels were positively but nonsignificantly correlated (r=0.04, r=0.1, r=0.13, r=0.00, respectively; p>0.05). HCV RNA and transferrin, A1AG were negative and nonsignificantly correlated (r=-0.22, r=-0.125, respectively; p>0.05). ALT and A1AG levels were negatively and nonsignificantly correlated (r=-0.18, p>0.05). ALT and albumin levels were negatively but significantly correlated (r=-0.37, p<0.05).
HCV RNA and CRP, transferrin, A2MG levels at the 48th week were positively but nonsignificantly correlated (r=0.11, r=0.03, r=0.33, respectively; p>0,05). ALT and CRP, transferrin, A1AG, albumin levels were negatively and nonsignificantly correlated (r=-0.16, r=-0.05, r=-0.21, r=-0.29, respectively; p>0.05). HCV RNA and ferritin, A1AG levels were negative and nonsignificantly correlated (r=-0.02, r=-0.17, respectively; p>0.05). ALT and ferritin levels were positively and significantly correlated (r=0.53, p<0.05). ALT and A2MG levels were positively and nonsignificantly correlated (r=0.05, p>0.05). HCV RNA and albumin levels were negatively but significantly correlated (r=-0.75, p<0.05).
DISCUSSION
Acute phase reactants (APRs) plays vital role on the regulation of inflammation and repairment of tissue damage.13 Synthesis and catabolism of APR is regulated by interleukin (IL-1, IL-6, IL-11), tumor necrosis factor (TNF), leukemia inhibitor factor, and oncostatin M. Tissue damage is associated with acceleration of positive APR (ceruloplasmin, C3, A1AG, A2MG, alpha-1 antitrypsin, alpha-1 antichymotrypsin, fibrinogen, haptoglobulin, CRP, and serum amyloid A protein) or deceleration of negative APR (prealbumin, albumin, transferrin, and alpha-2 glycoprotein) synthesis.14 Tsui et al.15 found HCV seropositivity to be associated with lower lipids, CRP and fibrinogen levels, and higher levels of IL-6 and TNF-α.
Liver biopsy is an invasive procedure that has been associated with complications; morbidity risk of 0.3% to 0.6% and mortality risk of 0.05%. Bourliere et al.16 combined noninvasive procedures like Fibroscan and Hepascore (Echosens, Paris, France), and concluded that diagnostic accuracy was increased and necessitance of liver biopsy was diminished.
HCV RNA and ALT are recent virologic and biochemical parameters to evaluate response to treatment in CHC. Early virologic response is determined by negative HCV RNA or reduction of 2 log by PCR analysis at the 12th week of therapy.17 APR may provide supplementary data as a cost-effective and feasible parameter in patients with CHC and may predict the response to therapy.
Patients with chronic viral hepatitis have increased levels of IL-1 and TNF-α; and elevated levels of cytokines stimulate the production of CRP. However, exact role of CRP on the progression of hepatitis is still unknown and remains to be determined. Shima et al.18 compared CRP levels of patients with chronic hepatitis B (CHB) or CHC and mentioned correlation between CRP and histologic activity in patients with CHB. Significant correlation exists between serum ALT and CRP levels and also between disease progression and CRP in patients with CHB. However, it was nonsignificant in patients with CHC. In contrast to patients with nonA-nonB hepatitis, Atono et al.19 determined significantly higher levels of CRP in patients with acute hepatitis A or B. Huang et al.20 determined significantly higher high-sensitivity CRP (hsCRP) levels in a study conducted on 95 patients with CHC and 95 healthy controls, and also achieved significant decrease in hsCRP level following to treatment with pegylated IFN and ribavirin. Bíró et al.21 examined the effect of IFN-α-2b therapy on APRs. They observed elevated complemant proteins (C-9 and C1-INH) subsequent to antiviral therapy for 3 months. Increment in C-9 and C1-INH was strongly correlated with virological response.21 In our study, CRP levels were similar between patients with CHC and healthy control group however decrease in CRP levels between initial evaluation and 4th and 12th week was significant (p=0.005 and p=0.014, respectively).
Alcoholic patients with CHC have diminished response to IFN therapy and significantly higher levels of CRP than nonalcoholic patients with CHC subsequent to IFN therapy.22 Lapinski23 carried out a study in 20 patients with CHC that underwent to IFN-α-2a therapy and determined no significant difference between CRP and albumin levels at the 2nd and 12th week. We observed no significant difference between responders and nonresponders in terms of CRP levels at baseline evaluation and 12th week. Elevation of CRP was significant between baseline evaluation and 4th or 12th week; however, difference between baseline evaluation and 48th week was nonsignificant. In contrast to previous reports, IFN use is considered to be the cause of elevation of CRP levels.
Ferritin levels were significantly higher in patients with CHC than healthy control group; similar to published data.24 Stam et al.25 emphasized that IFN therapy is related with increase of synthesis and secretion of ferritin. Exact mechanism of elevation of ferritin levels subsequent to IFN therapy is unknown; however, it is possibly related with liver tissue damage. Some other recent reports mentioned that combined IFN and ribavirin therapy is associated with decrease in the levels of serum iron, ferritin, transferrin, and increase amount of transferrin receptor.26 Our patients exhibit significantly higher ferritin levels at 4th, 12th, and 48th week. Early virologic response was evaluated at the 12th week and ferritin levels of responders were nonsignificantly higher than nonresponders. No significant correlation was observed between HCV RNA and ferritin levels. Elevated ferritin level is considered to be related with IFN therapy.
Nonresponders to IFN therapy have high levels of iron saturation.27 Hepatic fibrogenesis is stimulated by both liver tissue damage by viral infection induced oxygen radicals and increased liver iron storage.28 In a study from Turkey, 21 and 19 patients underwent to IFN+desferrioxamine and IFN alone, respectively.29 Ferritin and HCV RNA levels were significantly lower and histologic activity was better in the former group. Serum iron, ferritin levels and transferrin saturation were significantly higher in African-Americans with CHC and response to IFN therapy was significantly poorer in this group of patients.30 In contrast to relation of liver iron concentration and response to therapy, elevated level of ferritin is associated with poorer response to therapy (combined ribavirin and pegIFN therapy).31 Significant relation exist between serum iron level and hepatic fibrosis in patients with CHC. Serum ferritin level indicates the severity of hepatic fibrosis; independent from liver iron deposition.32 Serum iron level and liver iron storage are extremely high in IFN-nonresponders. Excessive iron load leads to poorer response to IFN however improves by iron chelation.33 Ferritin levels of our patients that response to IFN were nonsignificantly lower than nonresponders. The presence of increased hepatic iron, which is present in 30% to 40% of patients with CHC, has been linked to more severe liver disease and poorer response to IFN monotherapy. Iron depletion by phlebotomy has been shown to be associated with decreased incidence of decompensation and HCC.15
Serum transferrin levels exhibit hepatic iron load and related with poorer response to IFN therapy.33 Kalabay et al.34 performed a study in 40 patients with CHC that underwent to IFN-α-2b therapy. Patients responsive to treatment had significantly lower levels of transferrin than unresponsive group; however, CRP levels were similar between two groups.34 Patients with CHC usually higher levels of transferrin saturation.33 Iron load influences the natural course of HCV infection by leading to hepatic dysfunction and macrophage activation.35 Combined IFN and ribavirin therapy decreases serum iron, ferritin, and transferrin levels and increases the density of transferrin receptors.26 Transferrin levels of our patients significantly decreased from baseline point to 48th week. No significant difference was observed between transferrin levels of responders and nonresponders at the 12th week of therapy. This may be related to the fact that responders had higher transferrin levels at the initial evaluation.
A2MG, haptoglobulin, gammaglutamyl transferase (GGT) and total bilirubin are serum predictors of hepatic fibrosis.36 A2MG is an APR; produced by hepatocytes and stellate cells, inhibits catabolism of matrix proteins and hepatic fibrosis. Fibrogenesis and cytokine induced hepatocyte growth factor stimulates the synthesis of A2MG while inhibiting the synthesis of haptoglobulin.36 Patel et al.37 determined high levels of A2MG in patients with moderate to severe fibrosis. Patients with chronic persistant hepatitis and cirrhosis have increased density of lymphocytes and fibroblasts in liver tissue and higher levels of serum IgG and A2MG.38 Poynard et al.39 stated that serum markers like A2MG, haptoglobulin, GGT, and total bilirubin may have a predictive role on the progression of fibrosis and virologic response in patients with CHC without possible harmful effects of invasive methods such as liver biopsy. Ho et al.40 carried out a study to assess the predictive role of noninvasive serologic biomarkers such as A2MG, vitamin D binding protein (VDBP) and apolipoprotein AI (ApoAI). They revealed that the serum concentration of A2MG significantly increased from mild to advanced fibrosis however the protein levels of VDBP and ApoAI were significantly higher in normal or mild fibrosis, when compared to those in advanced fibrosis (both p<0.01). A2MG levels were significantly higher in our patients with CHC than healthy control group. Nonresponders had nonsignificantly higher levels of A2MG than responders. A2MG levels of our patients significantly decreased at the 4th and 12th week of treatment; however, it did not remain stable at the 48th week.
Serum albumin level and thrombocyte count indicate the severity of liver damage.41 Thrombocyte count lower than 140,000/mm3, AST/ALT >1, globulin/albumin >1 are considered to be the predictors of progression to cirrhosis.42 Volchkova et al.43 reported that patients with acute viral hepatitis have low levels of albumin, prealbumin, transferrin and high levels of haptoglobulin. However, patients with CHC had low levels of haptoglobulin as well as the other markers. No significant difference was observed in terms of albumin levels at the 4th, 12th, and 48th week. Nonresponders had nonsignificantly but remarkbly lower albumin levels than responders at the baseline evaluation (p=0.054). Negative correlation exist between HCV RNA and albumin levels at the 48th week and between ALT and albumin levels at the 12th week. Low albumin levels at the baseline evaluation is associated with poorer response to therapy.
A1AG, an internal membrane protein related with collagen overproduction, is synthesized by neutrophils, lymphocytes, monocytes, and hepatocytes. Stam et al.25 established elevated A1AG levels at the 4th week and at the 6th month of IFN-α-2b therapy.26 Nonresponders had higher A1AG levels at the 12th week when compared to responders. There was a significant increase in A1AG levels during treatment period however nonresponders exhibit remarkably higher increase in A1AG levels. Patients with CHC have increased levels of A1AG; however, elevation of A1AG subsequent to antiviral therapy is considered to associated with effect of IFN.
The present study has some limitations. First, sample size in our study was relatively low. Statistical significance may be enhanced by increasing sample size. Second limitation of the study was that ALT and HCV RNA are globally accepted parameters in predicting response to treatment in patients with CHC. However combining ALT and HCV RNA with APP may be more accurate to predict response to antiviral therapy. Third, patients in our study have different duration of CHC. Heterogenity in the duration of CHC may have significant impact on response to treatment. Also racial factors may play important in response to antiviral therapy. Ioannou et al.30 mentioned the effect of race and stated African-American patients with CHC exhibit poorer response to IFN therapy when compared to patients from other origin.
In conclusion, variations of ferritin, A2MG, albumin, CRP, transferrin, and A1AG levels would not be an alternative to virologic and biochemical parameters as a predictor of early response to therapy in patients with CHC. However these parameters may provide supplementary data in predicting response to treatment. Further studies with large number of individuals are required to establish these data.
Footnotes
No potential conflict of interest relevant to this article was reported.
References
- 1.Kim WR. The burden of hepatitis C in the United States. Hepatology. 2002;36(5 Suppl 1):S30–S34. doi: 10.1053/jhep.2002.36791. [DOI] [PubMed] [Google Scholar]
- 2.Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958–965. doi: 10.1016/s0140-6736(01)06102-5. [DOI] [PubMed] [Google Scholar]
- 3.Poynard T, Yuen MF, Ratziu V, Lai CL. Viral hepatitis C. Lancet. 2003;362:2095–2100. doi: 10.1016/s0140-6736(03)15109-4. [DOI] [PubMed] [Google Scholar]
- 4.Radziewicz H, Ibegbu CC, Hon H, et al. Transient CD86 expression on hepatitis C virus-specific CD8+ T cells in acute infection is linked to sufficient IL-2 signaling. J Immunol. 2010;184:2410–2422. doi: 10.4049/jimmunol.0902994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Fontana RJ, Israel J, LeClair P, et al. Iron reduction before and during interferon therapy of chronic hepatitis C: results of a multicenter, randomized, controlled trial. Hepatology. 2000;31:730–736. doi: 10.1002/hep.510310325. [DOI] [PubMed] [Google Scholar]
- 6.Smith BC, Gorve J, Guzail MA, et al. Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C. Hepatology. 1998;27:1695–1699. doi: 10.1002/hep.510270631. [DOI] [PubMed] [Google Scholar]
- 7.Valenti L, Pulixi EA, Arosio P, et al. Relative contribution of iron genes, dysmetabolism and hepatitis C virus (HCV) in the pathogenesis of altered iron regulation in HCV chronic hepatitis. Haematologica. 2007;92:1037–1042. doi: 10.3324/haematol.11281. [DOI] [PubMed] [Google Scholar]
- 8.Naveau S, Poynard T, Benattar C, Bedossa P, Chaput JC. Alpha-2-macroglobulin and hepatic fibrosis. Diagnostic interest. Dig Dis Sci. 1994;39:2426–2432. doi: 10.1007/BF02087661. [DOI] [PubMed] [Google Scholar]
- 9.Tiggelman AM, Boers W, Moorman AF, et al. Localization of alpha 2-macroglobulin protein and messenger RNA in rat liver fibrosis: evidence for the synthesis of alpha 2-macroglobulin within Schistosoma mansoni egg granulomas. Hepatology. 1996;23:1260–1267. doi: 10.1002/hep.510230547. [DOI] [PubMed] [Google Scholar]
- 10.Jang JY, Chung RT. Chronic hepatitis C. Gut Liver. 2011;5:117–132. doi: 10.5009/gnl.2011.5.2.117. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Lindsay KL. Introduction to therapy of hepatitis C. Hepatology. 2002;36(5 Suppl 1):S114–S120. doi: 10.1053/jhep.2002.36226. [DOI] [PubMed] [Google Scholar]
- 12.Jonsson JR, Barrie HD, O'Rourke P, Clouston AD, Powell EE. Obesity and steatosis influence serum and hepatic inflammatory markers in chronic hepatitis C. Hepatology. 2008;48:80–87. doi: 10.1002/hep.22311. [DOI] [PubMed] [Google Scholar]
- 13.Ait-Goughoulte M, Banerjee A, Meyer K, et al. Hepatitis C virus core protein interacts with fibrinogen-beta and attenuates cytokine stimulated acute-phase response. Hepatology. 2010;51:1505–1513. doi: 10.1002/hep.23502. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Akkus I, Gurbilek M, Caglayan O. Clinical biochemistrical laboratory handbook. Istanbul: Oz Egitim Basım Yayın Dagıtım Ltd. Sti.; 1997. pp. 15–55. [Google Scholar]
- 15.Tsui JI, Whooley MA, Monto A, Seal K, Tien PC, Shlipak M. Association of hepatitis C virus seropositivity with inflammatory markers and heart failure in persons with coronary heart disease: data from the Heart and Soul study. J Card Fail. 2009;15:451–456. doi: 10.1016/j.cardfail.2008.12.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Bourliere M, Penaranda G, Ouzan D, et al. Optimized stepwise combination algorithms of non-invasive liver fibrosis scores including Hepascore in hepatitis C virus patients. Aliment Pharmacol Ther. 2008;28:458–467. doi: 10.1111/j.1365-2036.2008.03742.x. [DOI] [PubMed] [Google Scholar]
- 17.Jang JY, Chung RT. Chronic hepatitis C. Gut Liver. 2011;5:117–132. doi: 10.5009/gnl.2011.5.2.117. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Shima M, Nakao M, Kato Y, et al. Comparative study of C-reactive protein in chronic hepatitis B and hepatitis C. Tohoku J Exp Med. 1996;178:287–297. doi: 10.1620/tjem.178.287. [DOI] [PubMed] [Google Scholar]
- 19.Atono Y, Sata M, Tanikawa K. Kinetics of C-reactive protein in acute viral hepatitis. Gastroenterol Jpn. 1989;24:655–662. doi: 10.1007/BF02774164. [DOI] [PubMed] [Google Scholar]
- 20.Huang CF, Hsieh MY, Yang JF, et al. Serum hs-CRP was correlated with treatment response to pegylated interferon and ribavirin combination therapy in chronic hepatitis C patients. Hepatol Int. 2010;4:621–627. doi: 10.1007/s12072-010-9200-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Bíró L, Varga L, Pár A, et al. Changes in the acute phase complement component and IL-6 levels in patients with chronic hepatitis C receiving interferon alpha-2b. Immunol Lett. 2000;72:69–74. doi: 10.1016/s0165-2478(00)00183-8. [DOI] [PubMed] [Google Scholar]
- 22.Ono K, Sata M, Murashima S, Fukuizumi K, Suzuki H, Tanikawa K. Biological responses to administered interferon in alcoholics. Alcohol Clin Exp Res. 1996;20:1560–1563. doi: 10.1111/j.1530-0277.1996.tb01699.x. [DOI] [PubMed] [Google Scholar]
- 23.Lapinski TW. Activation of acute phase proteins in patients with chronic hepatitis C treated with interferon-alpha 2a. Pol Merkur Lekarski. 2001;10:138–142. [PubMed] [Google Scholar]
- 24.Bolewska B, Wojtacha A, Juszczyk J, Przedwojewski M. Serum iron parameters in chronic hepatitis C patients and comparison of the results before and during antiviral treatment. Pol Merkur Lekarski. 2005;18:552–555. [PubMed] [Google Scholar]
- 25.Stam TC, Swaak AJ, Kruit WH, Eggermont AM. Regulation of ferritin: a specific role for interferon-alpha (IFN-alpha)? The acute phase response in patients treated with IFN-alpha-2b. Eur J Clin Invest. 2002;32(Suppl 1):79–83. doi: 10.1046/j.1365-2362.2002.0320s1079.x. [DOI] [PubMed] [Google Scholar]
- 26.Mozer-Lisewska I, Mania A, Kowala-Piaskowska A, Figlerowicz M, Sluzewski W. Alterations of soluble transferrin receptor level in children with chronic hepatitis C during treatment with recombinant interferon-alpha and ribavirin. Hepatol Res. 2005;33:19–23. doi: 10.1016/j.hepres.2005.08.001. [DOI] [PubMed] [Google Scholar]
- 27.Martín-Vivaldi R, Nogueras F, González A, et al. Response of chronic hepatitis C to interferon-alpha treatment and relationship with iron metabolism. Rev Esp Enferm Dig. 1997;89:523–530. [PubMed] [Google Scholar]
- 28.Casaril M, Stanzial AM, Tognella P, et al. Role of iron load on fibrogenesis in chronic hepatitis C. Hepatogastroenterology. 2000;47:220–225. [PubMed] [Google Scholar]
- 29.Bayraktar Y, Saglam F, Temizer A, Uzunalimodlu B, van Thiel DH. The effect of interferon and desferrioxamine on serum ferritin and hepatic iron concentrations in chronic hepatitis B. Hepatogastroenterology. 1998;45:2322–2327. [PubMed] [Google Scholar]
- 30.Ioannou GN, Dominitz JA, Weiss NS, Heagerty PJ, Kowdley KV. Racial differences in the relationship between hepatitis C infection and iron stores. Hepatology. 2003;37:795–801. doi: 10.1053/jhep.2003.50147. [DOI] [PubMed] [Google Scholar]
- 31.Hofer H, Osterreicher C, Jessner W, et al. Hepatic iron concentration does not predict response to standard and pegylated-IFN/ribavirin therapy in patients with chronic hepatitis C. J Hepatol. 2004;40:1018–1022. doi: 10.1016/j.jhep.2004.02.030. [DOI] [PubMed] [Google Scholar]
- 32.Metwally MA, Zein CO, Zein NN. Clinical significance of hepatic iron deposition and serum iron values in patients with chronic hepatitis C infection. Am J Gastroenterol. 2004;99:286–291. doi: 10.1111/j.1572-0241.2004.04049.x. [DOI] [PubMed] [Google Scholar]
- 33.Arber N, Moshkowitz M, Konikoff F, et al. Elevated serum iron predicts poor response to interferon treatment in patients with chronic HCV infection. Dig Dis Sci. 1995;40:2431–2433. doi: 10.1007/BF02063249. [DOI] [PubMed] [Google Scholar]
- 34.Kalabay L, Nemesánszky E, Csepregi A, et al. Paradoxical alteration of acute-phase protein levels in patients with chronic hepatitis C treated with IFN-alpha2b. Int Immunol. 2004;16:51–54. doi: 10.1093/intimm/dxh024. [DOI] [PubMed] [Google Scholar]
- 35.Weiss G, Umlauft F, Urbanek M, et al. Associations between cellular immune effector function, iron metabolism, and disease activity in patients with chronic hepatitis C virus infection. J Infect Dis. 1999;180:1452–1458. doi: 10.1086/315052. [DOI] [PubMed] [Google Scholar]
- 36.Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet. 2001;357:1069–1075. doi: 10.1016/S0140-6736(00)04258-6. [DOI] [PubMed] [Google Scholar]
- 37.Patel K, Gordon SC, Jacobson I, et al. Evaluation of a panel of non-invasive serum markers to differentiate mild from moderate-to-advanced liver fibrosis in chronic hepatitis C patients. J Hepatol. 2004;41:935–942. doi: 10.1016/j.jhep.2004.08.008. [DOI] [PubMed] [Google Scholar]
- 38.Fehér J, Jakab L, Józsa L, Szilvási I, Papp G. Serum immunoglobulin and glycoprotein concentration and mesenchymal reaction in chronic hepatitis and liver cirrhosis. Morphol Igazsagugyi Orv Sz. 1977;17:180–186. [PubMed] [Google Scholar]
- 39.Poynard T, Imbert-Bismut F, Ratziu V, et al. Biochemical markers of liver fibrosis in patients infected by hepatitis C virus: longitudinal validation in a randomized trial. J Viral Hepat. 2002;9:128–133. doi: 10.1046/j.1365-2893.2002.00341.x. [DOI] [PubMed] [Google Scholar]
- 40.Ho AS, Cheng CC, Lee SC, et al. Novel biomarkers predict liver fibrosis in hepatitis C patients: alpha 2 macroglobulin, vitamin D binding protein and apolipoprotein AI. J Biomed Sci. 2010;17:58. doi: 10.1186/1423-0127-17-58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Anderson S, Nevins CL, Green LK, El-Zimaity H, Anand BS. Assessment of liver histology in chronic alcoholics with and without hepatitis C virus infection. Dig Dis Sci. 2001;46:1393–1398. doi: 10.1023/a:1010671300507. [DOI] [PubMed] [Google Scholar]
- 42.Luo JC, Hwang SJ, Chang FY, et al. Simple blood tests can predict compensated liver cirrhosis in patients with chronic hepatitis C. Hepatogastroenterology. 2002;49:478–481. [PubMed] [Google Scholar]
- 43.Volchkova EV, Pak SG, Malov VA, Umbetova KT. Changes in the levels of acute phase proteins in viral hepatitis. Ter Arkh. 2000;72:18–21. [PubMed] [Google Scholar]